Some of the drugs that interact with DNA are among our most useful drugs in the treatment of neoplastic diseases. The agents and many derivatives bind to DNA and produce strand scission. We propose to develop a model to evaluate parameters of their actions and to use the model to study drug metabolism and activation in tumors and in tissues that are selectively intoxicated. Studies will be carried out with tumor cells, animals, membranes, mitochondria, and microsomes, and enzymes to define the systems of activation and to evaluate the means for control of their toxicity. The method of alkaline unwinding and hydroxyapatite chromatography, modified for batch elution, is used to determine DNA damage. The incorporation of thymidine into DNA is a parameter of nucleic acid synthesis (and repair) and drug metabolism is determined by HPLC and TLC. Studies with phospholipids and enzymes indicate biotransformation of the agents to forms that may be of more proximal to the final reactants which bind covalently to macromolecules.